1. Field of the Invention
Retinol (vitamin A) and retinoic acid (vitamin A acid), its isomers, and certain of its analogs are known to have beneficial effects in the treatment of acne and keratinizing skin disorders.
Acne affects large patient populations and is a common inflammatory skin disorder which usually localizes on the face. Fortunately, the disease usually disappears and in the interval of months or years between onset and resolution, therapy, although not curative, can satisfactorily suppress the disease in the majority of patients.
A small number of acne patients with severe disease show little or no response to intensive therapeutic efforts including the use of high doses of oral tetracycline, dapsone, prednisone and, in women, estrogen. In many cases, these drugs afford only a modest degree of control while the side effects of these agents severely restrict their usefulness. Patients with nodulocystic acne suffer from large, inflammatory, suppurative nodules appearing on the face, and frequently the back and chest. In addition to their appearance, the lesions are tender and often purulently exudative and hemorrhagic. Disfiguring scars are frequently inevitable.
Therapies for acne involve local and systemic administration of vitamin A compounds, collectively known as retinoids. Topical application of all-trans retinoic acid has been tried with some success, particularly against comedones or blackheads, but this condition frequently returns when the treatment is withdrawn. Additionally, retinoic acid applied topically can be highly irritating and its use can be painful for the patient depending on the concentration used and the frequency of application.
A number of side effects complicates the administration of large doses of vitamin A. Among the many symptoms of hypervitaminosis A are weight loss, desquamation of the skin, hair loss, irritation of the oral and pharyngeal mucosa, and nose bleeds, headaches, bone pain, liver toxicity due to storage of vitamin A in the liver, papilledena, pseudotumor cerebri, demineralization and periosteal thickening of bones. Because of these and other side effects oral treatment with vitamin A and all-trans retinoic acid, which produces similar side effects, is rarely recommended for dermatopathic conditions.
The present invention relates to an improved method of use of orally administered 13-cis-retinoic acid which unexpectedly results in the virtual elimination of severe chronic nodulocystic and conglobate acne, while at the same time it markedly reduces the side effects conventionally associated with oral retinoic acid therapies.
2. Description of the Prior Art
The successful use of 13-cis-retinoic acid, administered orally, for the treatment of cystic and conglobate acne was reported in Peck, et., "Prolonged Remissions of Cystic and Conglobate Acne with 13-cis-Retinoic Acid", New Eng. J. Med. 300:329-333 and 30:359-360, Feb. 15, 1979. In this study, a four month course of therapy with oral 13-cis-retinoic acid was begun at a minimum divided dosage of 1.0 mg per kilogram of body weight per day. The dosage was then increased in increments of 0.5 to 1.0 mg/kg/day at intervals of two to four weeks until either an appreciable therapeutic effect or dose-limiting toxicity was observed.
A report of the above study is also found in Gunby, "Synthetic Retinoid Used In Dermatopathies", J.A.M.A. 240:610, Aug. 18, 1978. In this report, it is further stated that the oral dosages used were from 80 to 240 mg/day of 13-cis-retinoic acid in capsule form with an average dose of 140 mg/day. Still another report of this study will be found in Peck, et al., "Treatment of Darier's Disease, Lamellar Ichthyosis, Pityriasis Rubra Pilaris, Cystic Acne and Basal Cell Carcinoma with Oral 13-cis-Retinoic Acid", Dermat. 157 (Suppl. 1):11-12 (1978).
Belgian Pat. No. 762,344 of Aug. 2, 1971, also discloses the use of orally administered 13-cis-retinoic acid for the treatment of acne (unspecified) and psoriasis. However, only a general dosage for various vitamin A compounds of from 0.1 mg to 0.5 mg to about 3.0 mg per kilogram of body weight is disclosed. Moreover, there is no example directed towards the use of 13-cis-retinoic acid.
In "Investigational Drug Brochure RO4-3780", printed by Hoffman-LaRoche Inc. sometime prior to the studies leading to the present invention, there appear several general statements indicating that all-trans retinoic acid had been used for oral treatment of acne, and that 13-cis-retinoic acid had proved to be less toxic than all-trans retinoic acid in animal experiments. There is also the statement that: "Skin diseases characterized by accelerated or pathological keratinization may respond to treatment with RO4-3780 (sic: 13-cis-retinoic acid), . . . as well as acne.". However, dosages were not discussed.
In a later edition of "Investigational Drug Brochure RO4-3780", Feb. 1978, there are statements mostly based upon the same studies that were the basis for U.S. patent application Ser. No. 63,770 filed Aug. 6, 1979. Specifically, it is disclosed that interest in the therapeutic applications of 13-cis-retinoic acid developed when preliminary testing indicated that it had epithelium-protecting ability equivalent to retinoic acid and was apparently less toxic. There is a further disclosure of the treatment of an unspecified acne with 13-cis-retinoic acid administered orally, but with no indication of the method of varying dosage which is the subject of this invention.
The "Handbook of Nonprescription Drugs", 5th ed., 1977, A.P.A. pub., Pp 140, 319, 320, discloses the use of vitamin A and retinoic acid, but not the 13-cis-stereoisomer, in the treatment of acne (unspecified). However, the disclosure of this publication is opposite to that of the subject invention, in that it states: "The systemic use of vitamin A for the treatment of acne, . . . is not warranted by clinical evidence." at page 140; and that: "Treatments that have been abandoned or have not been proved effective include oral vitamin A, . . . " at page 320.
J. V. Straumford reported a systemic usage of large oral doses of retinol, the alcohol form of vitamin A, over a long period of time for the treatment of acne (Straumford, J. V., "Vitamin A: Its Effect on Acne", Northwest Med., 42:219:255, August 1943). These results however have been disputed and systemic therapy of acne utilizing retinol has been challenged by other investigators (Anderson, J. A. D., et al., "Vitamin A in Acne Vulgaris", Brit. Med. J., 2:294-296, August, 1963; Lynch, F. W., et al., "Acne Vulgaris Treated with Vitamin A", Arch. Derm. 55:355, 357, March 1947; and Mitchell, G. H., et al., "Results of Treatment of Acne Vulgaris by Intramuscular Injections of Vitamin A", Arch. Derm. 64:428-434, October 1951).
Topical administration of retinoic acid for the treatment of acne was reported by Kligman, et al., (Arch. Derm. 99:469-476, 1969, U.S. Pat. No. 3,729,568). The effectiveness of this treatment as disclosed by Kligman is often associated with a noticeable irritating effect of topically applied retinoic acid.
The process for treating acne vulgaris topically utilizing retinal, the aldehyde form of vitamin A, is disclosed in U.S. Pat. No. 3,932,665. The aldehyde form, unlike the acid form of vitamin A, exerts its therapeutic effect without producing irritation, inflammation, erythema, or peeling of the skin. This patent also discloses the topical use of 13-cis-retinal in the treatment of acne vulgaris.
The method of treating acne with C-20 and C-22 vinylogs of desmethyl retinoic acid is disclosed in U.S. Pat. No. 3,882,244. These vinylogs as disclosed in the patent are applied topically to the site of the acne infection as a solution, ointment or powder. The treatment of acne vulgaris with retinoic acid analogs particularly 11-(2',6',6'-trimethylcyclohex-1'-enyl-1')-5,9-dimethylundeca-2,4,6,8,10-p entenoic acid is disclosed in U.S. Pat. No. 3,934,028. This compound can be used either internally or topically. When taken orally, the daily dosage of this compound ranged from 30-300 mg taken over from 2 to 8 weeks. However, there is no indication that the compounds leads to remission from the disease after administration of the compound is withdrawn.
Although 13-cis-retinoic acid is generally less toxic than all-trans retinoic acid, there are still precautions that must be observed in its use. With oral retinoic acid, headaches, nausea, vomiting, and some of the skin and mucous membrane lesions experienced with hypervitaminosis A have been reported. Because of chemical and pharmacological similarities between 13-cis-retinoic acid, retinoic acid and retinol, similar adverse reactions occur with 13-cis-retinoic acid. See Blackman, et al., "Blepharoconjunctivitis: Side Effect of Oral 13-cis-Retinoic Acid Therapy of Dermatologic Disease", Ophthal. 85:35, July 1978, and some of the above articles.